The prefrontal region and its function, working memory, are both impaired in schizophrenia. In order to fulfill the PI's long-term career goal of uncovering a biological basis of schizophrenia, the PI proposes to study local circuitry in primate prefrontal cortex and the neuronal signaling mechanisms underlying working memory in normal and pathological conditions. This career path promises to translate the understanding of functional circuit analysis into clinically relevant hypotheses of neuropathology in schizophrenia. The immediate project proposed here asks about local excitatory neuronal signaling and its modulation by dopamine in prefrontal cortex in normal nonhuman primates and in an amphetamine-treated monkey model of schizophrenia. Pyramidal-to-pyramidal and pyramidal-to-nonpyramidal connections will be studied in a novel in vitro living slice preparation using dual somatic recording via the whole cell patch clamp technique. Electrophysiological, pharmacological and anatomical analyses of these connections will be performed. The neuromodulatory effect of dopamine on identified excitatory and inhibitory synaptic transmission will be explored. Experiments will be conducted initially in ferrets and then in nonhuman primates and in human temporal cortex surgically removed for the treatment of intractable epilepsy. This project will allow a detailed examination of a realistic experimental unit of normal prefrontal cortical excitation in primates and a characterization of alterations in experimental nonhuman primate models of schizophrenia. The project will advance our understanding of the circuit basis of information processing mechanisms in the primate prefrontal cortex. The proposed multidisciplinary approach requires fundamental knowledge of electrophysiology, pharmacology, ion channels, statistics and electron microscopy, and the candidate's previous training is limited mostly to neuroanatomy. If this grant is awarded, the candidate will receive formal neuroscience coursework equivalent to a Ph.D. degree in neuroscience and conduct the proposed research projects in the rich scientific environment of the Center for Neuroscience of Mental Disorders.